Necrosis of Schwann cells during tellurium-induced primary demyelination: DNA fragmentation, reorganization of splicing machinery, and formation of intranuclear rods of actin

We present a cytological, immunocytochemical, and biochemical study of the cell death of mature myelinating Schwann cells (SCs) in the primary demyeli nating neuropathy induced by tellurium (Te). Weaned rats were fed a diet co ntaining 1.1% elemental Te. The animals were killed daily within the first week of Te diet. After 4 to 6 days of Te treatment some SCs underwent degen eration and necrosis, By electron microscopy analysis, degenerating SCs sho wed chromatin condensation, detachment from the nuclear envelope of condens ed chromatin clumps, aggregation of interchromatin granule clusters, format ion of intranuclear bundles of microfilaments, and cytoplasmic vesiculation . By confocal laser fluorescence microscopy, chromatin regions were stained with the TUNEL method for in situ labeling of DNA fragmentation and exhibi ted a progressive reduction of histone signal. In addition, splicing small nuclear ribonucleoprotein (snRNP) factors were redistributed in a few large nuclear domains and bright foci of intranuclear actin were observed. DNA e lectrophoresis revealed a smear pattern of DNA fragmentation in sciatic ner ve samples from Te-treated animals. Upon Te treatment, no degradation of th e caspase substrates poly (ADP-ribose) polymerase and lamin B was detected by Western blots or immunocytochemistry, respectively. The peculiar structu ral rearrangement of the transcription and splicing machinery as well as th e vesicular degeneration of the cytoplasm in degenerating SCs support an au tophagic cell death of the necrotic type. Unlike the apoptosis of pre-remye linating SCs (11), this caspase independent cell death of necrotic type inv olves mature pre-demyelinating SCs and eliminates SCs injured by the neurot oxic effect of Te.